This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality in the United States (1). COPD is a heterogeneous syndrome, with varying contributions of emphysema and airway disease in each COPD subject. Genetic studies of complex diseases like COPD have the potential to provide insight into the pathophysiological mechanisms of COPD susceptibility and heterogeneity. A strong genetic basis for the susceptibility of smokers to develop COPD is suggested by: 1) Marked variability in the development of airflow obstruction among smokers (2);2) Clear familial clustering of COPD and COPD-related phenotypes (3);and 3) Linkage of COPD-related phenotypes to specific genomic regions in families with severe, early-onset COPD (4). Case-control studies have been performed for many candidate genes in COPD, but the results have been inconsistent (5). Possible contributors to these inconsistent results include: 1) small sample sizes;2) inadequate classification of distinct phenotypes (e.g., emphysema vs. airway disease);3) widely varying criteria used for case definition and control selection in different studies;4) failure to assess (and, if necessary, adjust) for population stratification;5) testing a limited number of genetic variants in each candidate gene;6) genotyping error;and 7) lack of correction for multiple statistical testing. Recent progress in single nucleotide polymorphism (SNP) genotyping allows for association studies on a genome-wide scale, rather than limiting analysis to recognized candidate genes or regions of linkage;however, the multiple statistical tests involved in genome-wide association (GWA) studies of thousands of SNPs raise challenges in separating true from false positive associations (6). In addition, genetic association studies within a single racial/ethnic group may not generalize to other populations. To address the multiple testing and generalizability problems of GWA studies, we propose to perform a comprehensive GWA study to identify genes influencing COPD in two major racial/ethnic groups (non-Hispanic Whites and African Americans). Our primary hypotheses are: (1) Precise characterization of COPD subjects using computed tomography, as well as clinical and physiological measures, will provide insight that will enable the broad COPD syndrome to be decomposed into clinically significant subtypes. (2) Genome-wide association studies will identify genetic determinants for COPD susceptibility that will provide insight into clinically relevant COPD subtypes. (3) Distinct genetic determinants influence the development of emphysema and airway disease. II. SPECIFIC AIMS Specific Aim 1: Cohort Building Identify and phenotype 6,000 COPD cases and 4,500 control subjects from two racial/ethnic groups (non-Hispanic Whites and African Americans) for genetic, epidemiologic, and natural history studies. Specific Aim 2: Genome-Wide Association Study a. Phase 1. A genome-wide panel of SNPs will be tested for association with COPD in case-control samples from non-Hispanic Whites and African-Americans. b. Phase 2. Confirmation of SNPs yielding association signals in a second case-control population from the same racial/ethnic group to identify genomic regions for intensive investigation. c. Phase 3. Mapping of fifty genomic regions yielding strong, confirmed association signals in a third case-control population from the same racial/ethnic group to identify susceptibility genes for COPD. d. Phase 4. Fine mapping of candidate genes to identify susceptibility alleles and/or high risk haplotypes using multiple study designs and independent samples, including: + Entire set of case-control samples from both racial/ethnic groups + External validation using family-based association analysis in the Boston Early-Onset COPD Study and the International COPD Genetics Network Specific Aim 3: Characterization of Subtypes of COPD a. To further characterize the unique airway and parenchymal phenotypes of COPD by determining their associations with clinical, physiologic and functional indices. b. Identify susceptibility genes for COPD subtypes, including CT-defined emphysema and CT-defined airway disease.